Claims:

1. A photosensitizer composition comprising; a) tetrapyrrole and its
derivatives, selected from the group consisting of porphyrins, chlorins,
pheophorbides and bacteriopheophorbides; and b) appropriate excipients
and carriers.

2. The photosensitizer composition according to claim 1, wherein said
excipients and carriers are selected in relation to the pharmaceutical
dosage form adopted according to the route of administration selected.

3. The photosensitizer composition according to claim 1, wherein said
photosensitizer is Temoporfin (m-THPC).

4. An applicator for colorectal PDT treatment comprising; a) a
hollow-shaped element with at least one center conduit; b) at least two
conduits placed opposite each other at the surface of said hollow-shaped
element parallel to said center conduit; and c) at least two conduits
with a slope.

5. The applicator of claim 4, wherein adjustable spacers may be placed in
the conduits to prevent damage to the anal mucosa by inserting
measurement probes.

6. The applicator of claim 4, wherein said conduit's slope is about 35
degrees.

7. The applicator of claim 4, further comprising a material which is used
to monitor the fluence rate at the same time as doing optical
spectroscopy.

8. The applicator of claim 4, wherein said material is a polymeric
material which has a Raman peak from a C-H stretch/an amide group.

9. A measurement probe device comprising, a) a hollow element of
medical-grade metal; b) at least two waveguides, placed at a determined
core-to-core distance of said hollow element of medical-grade metal; and
c) a fluorescence differential path length spectroscopy control unit.

10. The measurement probe device according to claim 9, wherein said
waveguides have a slope at distal tips.

11. The measurement probe device according to claim 10, wherein said
slope at the tip is about 35 degrees.

12. The measurement probe device according to claim 9, wherein at least
one of said waveguides is a radiation delivery and radiation collector
optical fiber.

13. The measurement probe device according to claim 9, wherein said
hollow element of medical-grade metal is a stainless steel needle.

14. The measurement probe device according to claim 9, wherein at least
one of said waveguide is a radiation collector optical fiber.

15. A device for colorectal PDT treatment comprising; a) at least one
radiation source; b) a multichannel dosimetry device; c) a long pass
filter; d) at least one waveguide; and e) at least one measurement probe.

16. The device for colorectal PDT treatments according to claim 15,
wherein said radiation source is a coherent or incoherent radiation
source selected from the group consisting of lasers, white light sources,
light emitting diodes, lamps, and a combination of these whose output can
be regulated within a preselected spectral window.

17. The device for colorectal PDT treatments according to claim 15,
wherein said at least one waveguide is an optical fiber selected from the
group consisting of radial optical fibers, linear diffusers, balloon
optical fibers, bifurcated optical fibers and combination of these.

18. The device for colorectal PDT treatments according to claim 15,
wherein said radiation source is a laser radiation source operating at
about 400 to about 800 nm.

19. The device for colorectal PDT treatments according to claim 15,
wherein said radiation source is an excitation laser radiation source
operating at about 650 nm for fluorescence measurements.

20. The device for colorectal PDT treatments according to claim 19,
wherein said excitation laser radiation source is used with one or more
laser beam splitters.

21. The device for colorectal PDT treatments according to claim 19,
wherein means for shutter is placed in laser radiation path to control
the excitation laser radiation for each measurement probe.

22. The device for colorectal PDT treatments according to claim 21,
wherein said measurement probe is a measurement probe device whose
outputs are processed with the aid of a fluorescence differential path
length spectroscopy control unit.

24. A dynamic colorectal PDT method comprising the steps of a)
administering an effective dose of a photosensitizer composition; b)
placing at least one measurement probe and at least one treatment
waveguide at a treatment site; c) irradiating said treatment site; and d)
monitoring treatment parameters before, during and/or after irradiation.

25. The dynamic colorectal PDT method according to claim 24, wherein said
method is to treat abnormal cell growth in anal tissue selected form the
group consisting of perianal intraepithelial neoplasia grade III and
intra-anal intraepithelial neoplasia grade 3.

26. The dynamic colorectal PDT method according to claim 24, wherein said
photosensitizer composition is administrated topically, intravenously,
orally or a combination of these.

27. The dynamic colorectal PDT method according to claim 24, wherein said
at least one measurement probe is selected from the group consisting of
passive probes, active probes and a combination of these.

28. The dynamic colorectal PDT method according to claim 24, wherein said
at least one treatment waveguide is an optical fiber selected from the
group consisting of radial optical fibers, linear diffusers, balloon
optical fibers and combination of these.

29. The dynamic colorectal PDT method according to claim 24, wherein said
treatment parameters monitored include explicit and implicit parameters
and are selected from the group consisting of fluence, fluence rate,
fluorescence, photosensitizer concentration, tissue oxygenation,
saturation, blood volume and combinations of these.

[0003] The present invention relates to the treatment of abnormal cell
growth in the gastrointestinal tract. More particularly, present
invention relates to methods, devices and compositions containing
hydrophobic photosensitizers for photodynamic therapy for the treatment
of unwanted cells and tissues of the intra-anal and perianal region such
as anal intraepithelial neoplasia grade III (high grade dysplasia).

[0004] 2. Invention Disclosure Statement

[0005] Anal intraepithelial neoplasia (AIN) or anal dysplasia is an
abnormal cell growth in anal tissue that in some cases may progress to
cancer. Depending on how the cells look under the microscope, AIN may be
further subdivided into AIN Grade I, AIN Grade II and AIN Grade III. The
term anal squamous intraepithelial lesions (ASIL) is also used to
describe AIN; which can be further classified as low-grade squamous
intraepithelial lesions (LSIL) equivalent to AIN I (mild dysplasia), and
high-grade squamous intraepithelial lesions (HSIL) which includes AIN II
(moderate dysplasia) and AIN III (severe dysplasia). Additionally, the
terms anal carcinoma in situ (Stage 0, National Cancer Institute's
classification system) and Bowens disease of the anus can also be found
in literature, which are sometimes used to denote HSIL. Although LSIL are
not thought to be a direct precursor to anal cancer, they may progress to
HSIL. On the other hand, HSIL is a progressive, potentially precancerous
condition that requires attention; a small proportion of AIN III-type
lesions that are not treated or removed may develop into invasive cancer,
destroying adjacent tissues and/or organs and ultimately causing death.
For this reason it is advantageous to screen for AIN III and treat before
it can progress to invasive anal cancer.

[0006] To date the management of AIN III lacks accepted treatment
protocols. Current treatment modalities for AIN III are electrocautery,
cryosurgery and excision but such therapies can result in significant
pain or postoperative complications including anal stenosis and severe
long-term side effects such as strictures, fecal incontinence and
colostomy. Furthermore, ablative treatments are often limited by a high
incidence of recurrence. Other treatment options include laser ablation,
which can only be used to treat small lesions, and immunomodulation,
lacking of sufficient long-term data on therapy results.

[0007] In an attempt to provide a method for treating anorectic disorders,
Ehrenpreis discloses in U.S. Pat. No. 7,250,445 a method comprising a
step of providing a suppository containing between 1000 and 500,000 IU
(international units of measure) of an antioxidant selected from the
group of Vitamin A, Vitamin C, and Vitamin E; and a step of placing the
suppository within rectal cavity for a period of time required for
dissolution of the suppository. However, it only provides a substitute or
adjunct for conventional treatments for anorectic disorders when no
current therapies are available.

[0008] Another possible treatment modality, that has the potential for
curative treatment of AIN III with less long-term side effects, is PDT.
An additional and significant advantage of PDT is that it allows
therapeutic illumination of the whole surface of the anal cavity in a
single treatment session. This is of importance since other treatment
modalities show, based on their high recurrence rates of up to 50%, that
it is difficult to determine exactly where to treat for AIN III in the
anal cavity.

[0009] Photodynamic therapy has been successfully used for superficial,
intraluminal and interstitial treatment of (pre) malignant lesions in
among others dermatology, esophagus, lungs, head and neck, prostate and
vulva. There are a small number of clinical reports on PDT in the anal
region for treatment of perianal AIN III and carcinoma in situ using
topical or systemic administered ALA. Light delivery for perianal lesions
was done using a light delivery device that uses a mirror to direct
treatment light onto the treatment area (Hamdan K A, Tait I S, Nadeau V,
Padgett M, Carey F, Steele R J; Treatment of grade III anal
intraepithelial neoplasia with photodynamic therapy: report of a case;
Dis Colon Rectum.; 2003; 46:1555-9). For intra-anal treatment of
carcinoma in situ a rectal speculum was used to expose the mucosa.
Subsequently a linear diffuser was placed in the center of the speculum
for therapeutic illumination. Since the speculum shields half of the
tissue two illuminations are necessary where for the second illumination
the speculum is rotated 90 degrees (Webber J, Fromm D; Photodynamic
therapy for carcinoma in situ of the anus; Arch Surg.; 2004; 139:259-61).

[0010] Unfortunately, currently applicators used for PDT of the anal
cavity only facilitate the delivery of light to either the perianal or
intra-anal region and do not facilitate probes to monitor explicit and/or
implicit parameters to provide an insight of the relationship between the
treatment and tissue response in situ. Thus, it would be advantageous to
dynamically monitor explicit and implicit parameters during perianal or
intra-anal PDT treatment in order to aid in optimizing and standardizing
PDT therapy.

[0011] Due to the disadvantages of conventional treatment modalities and
previous PDT therapies of perianal and intra-anal AIN III, there is a
need to provide dynamically enhanced PDT treatments for safe and improved
clinical PDT treatment protocols.

OBJECTIVES AND BRIEF SUMMARY OF THE INVENTION

[0012] It is an objective of present invention to provide PDT methods,
devices and compositions for treatment of abnormal cell growth in anal
tissue such as perianal and intra-anal grade 3 Anal Intraepithelial
Neoplasia (AIN III).

[0014] Still another objective of present invention is to provide devices
for enhanced intra-anal PDT treatment for severe dysplasia such as AIN
III, providing means for enhanced delivery of electromagnetic radiation.

[0015] A further objective is to provide compositions containing
hydrophobic photosensitizers for colorectal photodynamic therapy for the
treatment of unwanted cells and tissues of the intra-anal and of the
perianal region.

[0016] Briefly stated, dynamic colorectal PDT methods, devices and
photosensitizer compositions to treat abnormal cell growth in anal tissue
such as perianal and intra-anal intraepithelial neoplasia grade III are
presented. A dynamic colorectal PDT method comprises the steps of
administering topically, intravenously or orally a photosensitizer
composition; irradiating; and monitoring treatment parameters before,
during and/or after irradiation. A photosensitizer composition comprises
Temoporfin (m-THPC) and excipients and carriers, appropriate for the
method of application. An applicator is provided for colorectal PDT
treatments to enhance irradiation delivery and monitor treatment
parameters. Preferably, said applicator is made of a material which is
used to monitor the fluence rate at the same time as doing optical
spectroscopy. Measurement probe devices are provided for monitoring PDT
treatment parameters in vivo. A device for colorectal PDT treatment is
also provided, comprising a laser radiation source operating at about 400
and 800 nm; an excitation laser radiation source operating at about 650
nm for fluorescence measurements; a multichannel dosimetry device; a long
pass filter; waveguides and measurement probes.

[0017] The above, and other objects, features and advantages of the
present invention will become apparent from the following description
read in conjunction with the accompanying drawings, in which like
reference numbers in different drawings designate the same elements.

BRIEF DESCRIPTION OF FIGURES

[0018] FIG. 1 illustrates a schematic longitudinal cross section of a
preferred embodiment showing the location of all optical fiber conduits
in the applicator.

[0019] FIG. 2 shows another preferred embodiment of a device for PDT
treatment of perianal and intra-anal AIN III.

[0021] FIG. 4 shows the normalized fluence rate as a function of length
for measurements along the applicator with all optical fibers at their
correct position; in which open squares correspond to measurements done
on the side where the measurement optical fibers were located and open
triangles on a side where no measurement optical fibers were located. The
solid line represents the fluence rate profile of the linear diffuser
used for treatment (i.e. measured outside the applicator).

[0022] FIG. 5 shows the measured fluence rate as a function of delivered
irradiation dose measured in situ at two locations (black and gray lines)
in a single patient.

[0023] FIG. 6 shows saturation (open diamonds) and blood volume (open
triangles) as a function of time measured during the course of treatment
in a patient with a delivered dose of 17 Jcm-2. The vertical lines
indicate start and end of therapeutic illumination.

[0025] FIG. 8 shows a long wavelength fluorescence spectrum acquired by a
1 cm linear diffuser (open circles), used for monitoring fluence (rate)
and fluorescence, with its fit (solid line) and residual, and the
individual components.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0026] The present invention provides PDT methods, devices and
compositions containing hydrophobic photosensitizers for treatment of
abnormal cell growth in anal tissue such as perianal and intra-anal grade
3 anal intraepithelial neoplasia (AIN III). A main advantage of present
invention is that it provides a safer and enhanced colorectal PDT
treatment of perianal and intra-anal AIN III due to the possibility of
monitoring in situ implicit and explicit parameters which allow a better
control of PDT treatment parameters. By monitoring implicit or explicit
parameters such as fluence, fluence rate, fluorescence, photosensitizer
concentration, tissue oxygenation, saturation and blood volume, a more
precise relationship between PDT treatment parameters and tissue response
in situ can be established. Additionally, a safe and homogenous
electromagnetic radiation delivery is obtained by using the devices
disclosed in the present invention.

[0027] In one embodiment, a colorectal PDT method for treatment of
peri-anal and intra-anal AIN III comprises the steps of: 1) administering
an effective dose of a photosensitizer composition; 2) placing at least
one measurement probe and at least one treatment waveguide in treatment
site; 3) irradiating said treatment site; and 4) monitoring treatment
parameters before, during and/or after irradiation. Before the
administration of a photosensitizer composition and after irradiation the
patient is maintained under subdued light conditions for a predetermined
time interval in order to avoid undesired and uncontrolled
photosensitizer activation. The time interval between the administration
of the photosensitizer composition and the irradiation step will
generally depend on the photosensitizer composition, dose, patient
condition and means of administration (topical, oral or involving any
part of the gastrointestinal tract, or intravenous administration). In
the case of intra-anal AIN III treatment, an applicator disclosed in
present invention is inserted in treatment area in order to access and
make contact with the unfolded and nearly unreachable unhealthy mucosa.
At least one treatment waveguide is an optical fiber selected from the
group consisting of radial fibers, linear diffusers, balloon fibers and
similar, providing that the tip of the optical fiber ensures a proper and
efficient delivery of radiation energy to the target tissue. Measurement
probes include, but are not limited to passive and/or active probes. In a
preferred embodiment, the measurement probe is a device disclosed in
present invention, defined as a fluorescence differential path length
spectroscopic (FDPS) probe. By placing the treatment waveguide(s) and the
measurement probe(s) in the anal cavity with the aid of present invention
applicator there is scarcely or no risk of damage or perforation of the
mucosa. In the case of intra-anal AIN III treatment, an occluding cloth
is placed at the base of present invention applicator to prevent
irradiation of normal skin around the perianal region. For perianal AIN
III treatment the irradiation region is carefully delimitated with the
aid of dark materials such as black paraffin or similar. The preferred
parameters monitored include but are not limited to fluence, fluence
rate, fluorescence, photosensitizer concentration, tissue oxygenation,
saturation and blood volume. The great advantage of measuring the fluence
rate in vivo at the anal wall is that the irradiation dose can be
accurately controlled while the treatment is performed, so possible
overtreatment of tissue is avoided, which can possibly lead to negative
side effects such as perforations or anal dysfunctions. Preferably,
fluence rate is measured in vivo at the anal wall at two opposite
locations. Once the required dose is achieved the irradiation step is
stopped and the applicator, waveguide(s) and measurement probe(s) are
removed from the treatment site. A significant advantage of the present
colorectal PDT method is that it allows therapeutic irradiation of the
whole surface of treatment site in a single treatment session, while
other employed treatment devices/methods have shown that is difficult to
determine exactly where to treat for AIN III in the anal cavity, and thus
under-treat some tissue and overtreat other tissue.

[0028] In a preferred embodiment, the photosensitizer composition includes
tetrapyrrole and their derivatives as photosensitizer and appropriate
excipients and carriers, depending on the pharmaceutical dosage form
adopted according to the route of administration selected. Preferably,
the photosensitizer is selected from the group consisting of porphyrins,
chlorins, pheophorbides and bacteriopheophorbides. In a most preferred
embodiment the photosensitizer exogenously administered is Temoporfin
(m-THPC).

[0029] One disadvantage of currently applicators used for PDT for the anal
cavity is that they only facilitate the delivery of radiation to the
intra-anal region; and do not facilitate probes to monitor explicit
parameters such as fluence, fluence rate, photosensitizer concentration,
tissue oxygenation, and/or implicit parameters such as fluorescence
photobleaching. Since the deposited PDT dose depends on the concentration
of photosensitizer, irradiation treatment parameters and the tissue
oxygen concentration, monitoring these parameters can give information
not only on delivered PDT dose but also provide an insight to the
relationship between PDT dose and tissue response. For this reason the
applicator of present invention provides means to monitor explicit and
implicit parameters which aid in optimizing and standardizing PDT
treatments and offers enhanced and safer PDT procedures. An applicator
for colorectal PDT treatment of present invention comprises a
hollowed-shape element with at least one center conduit; at least two
conduits placed opposite each other at the surface of said
hollowed-shaped element parallel to said center conduit; and at least two
conduits with a slope. Additionally, adjustable spacers may be placed in
the conduits to prevent damage to the anal mucosa by inserting
measurement probes. Preferably, measurement probes are fluorescence
differential path length spectroscopy (FDPS) measurement probes. In
addition, the applicator of present invention is preferably made of a
material which could be used to monitor the fluence rate at the same time
as doing optical spectroscopy. Preferably, said material is a polymeric
material which has a Raman peak from a C-H stretch that could usually be
identified as an amide group. In a preferred embodiment depicted in FIG.
1, applicator 100, which delivers radiation and monitors treatment
parameters for PDT treatments of intra-anal AIN III, comprises hollowed
cylinder with the shape of a clinical anoscope 102 which is a
hollowed-shape element preferably made of plastic, medical grade silicone
104 to fill in clinical anoscope 102; at least one center conduit 106 to
place at least one treatment waveguide, more preferably, treatment
optical fiber 108 and additional measurement conduits 110 to place
optical fiber probes. Preferably, there are at least four additional
measurement conduits 110. A pair of additional measurement conduits 110
are placed opposite each other at the surface of the applicator and
parallel to center conduit 106 in order to place linear diffusers 112 of
appropriate diffusing length based on the size of the lesion to measure
fluence rate and fluence at the anal mucosa; and another pair of
additional measurement conduits 110 are under a slope of 35 degrees to
facilitate contact of FDPS measurement probes 200 with the anal wall.
Preferably, the distal ends of FDPS measurement probes 200 are polished
under an angle of 35 degrees to minimize specular reflection between the
probe-tissue interface. Adjustable spacers may be placed on the FDPS
measurement probes 200 to prevent damage to the anal mucosa from
potentially inserting the FDPS measurement probes 200 too far. With this
configuration, the radiation distribution along the applicator is
homogeneous for the length of diffuser used for treatment. Furthermore,
due to the existence of measurement probes and their location in
different positions it is possible to provide a safer PDT treatment by
monitoring in situ treatment parameters that allows delivering the
appropriate PDT light dose while minimizing damage to surrounding healthy
tissue. Additionally, the applicator of present invention does not
influence, minimally or slightly influences the fluence rate profile of
the treatment waveguide, embodied as a treatment optical fiber.

[0030] Present invention also provides measurement probe devices, in order
to monitor implicit and explicit PDT treatment parameters, comprising a
hollow element of medical-grade metal; at least two waveguides, placed at
a predetermined core-to-core distance of said hollow element of
medical-grade metal; and a fluorescence differential path length
spectroscopy control unit. In this disclosure measurement probe devices
are also called FDPS measurement probes due to the control unit used to
process a range of treatment parameters. FIG. 2 shows schematically an
embodiment of FDPS measurement probe 200 comprising stainless steel
needle 214 which embodies a hollow element of medical-grade metal,
containing two waveguides, radiation delivery and collection optical
fiber 216 and collection optical fiber 218, both placed at a determined
core-to-core distance of the needle. Stainless steel needle 214,
radiation delivery and collection optical fiber 216 and collection
optical fiber 218 are polished under an angle of 35 degrees to minimize
specular reflection at the probe-tissue interface. This angle was chosen
to optimize probe-tissue contact in the current measurement/treatment
geometry in combination with the used treatment applicator, however,
other polished angles can also be chosen depending on the
measurement/treatment geometry and the treatment applicator used.
Radiation delivery and collection optical fiber 216 and collection
optical fiber 218 are connected to fluorescence differential path length
spectroscopy (FDPS) control unit 220.

[0032] Linear diffusing tip 326 is connected to the proximal end of
optical fiber 342. The distal end of optical fiber 342 is coupled to the
proximal end of bifurcated optical fiber 344. The distal end of
bifurcated optical fiber 344'' is connected to multichannel dosimetry
device 330. The distal end of bifurcated optical fiber 344' is connected
to long pass filter 332.

[0033] Excitation laser radiation source 324 is connected to the proximal
end of optical fiber 346. Shutter 336 is placed in laser radiation path
to control the excitation laser radiation. The distal end of optical
fiber 346 is coupled to the proximal end of bifurcated optical fiber 348.
The distal end of bifurcated optical fiber 348' is coupled to white light
radiation source 334 for FDPS measurements and bifurcated optical fiber
348'' is coupled to the proximal end of bifurcated optical fiber 350. The
distal end of bifurcated optical fiber 350' is connected to spectrograph
device 328. The distal end of bifurcated optical fiber 350'' is coupled
to the radiation delivery and collection optical fiber of FDPS
measurement probe 360.

[0034] In another embodiment, light dosimetry and long wavelength
fluorescence are measured with linear diffusing tips of 1 cm or isotropic
tips at the distal end of a 400 micron optical fiber. The other end of
the optical fiber is split using a 200/400 micron bifurcated fiber. The
200 micron arm of the bifurcated fiber is coupled into a modular based
multichannel dosimetry device. The 400 micron arm is coupled into a long
pass filtered, channel of a two-channel spectrograph, which blocks light
less than 690 nm wavelengths).

[0035] Apart from measuring treatment parameters in situ, in one
embodiment a data processing unit can be used in order to manage
fluorescence spectroscopy data, fluorescence differential path-length
spectroscopy data and signals measured with measurement probes. In one
embodiment, long wavelength fluorescence spectra are analyzed as a linear
combination of basis spectra using a singular value decomposition (SVD)
algorithm. The fluorescence can be described by a combination of
autofluorescence and m-THPC fluorescence, when this is the
photosensitizer used. The autofluorescence basis-spectrum can be defined
as the average of acquired spectra measured in a patient before m-THPC
was administered. The m-THPC basis-spectrum can be defined as the average
of spectra acquired in m-THPC administered patients with subtraction of
the autofluorescence signal. In the case of fluorescence differential
path-length spectroscopy data, differential fluorescence spectra can be
analyzed using the same SVD as for the long wavelength fluorescence with
the addition of a third component. The differential fluorescence spectra
contain contribution from the therapeutic laser. The residual laser light
in the fluorescence spectra can be described by a Gaussian, peak at 648
nm width 12.3 nm. The autofluorescence basis-spectrum is defined as the
average of spectra acquired in a patient before m-THPC was administered
and the m-THPC basis-spectrum is defined as the average of spectra
acquired in m-THPC administered patients with subtraction of the
autofluorescence and residual laser light. Additionally, the differential
reflectance signal is used to obtain values on saturation and blood
volume.

[0036] The present invention is further illustrated by the following
examples, but is not limited thereby.

Example 1

[0037] Patients with biopsy proven clinical intra-anal AIN III were
treated. Forty-eight hours before illumination patients were administered
with 0.075 mg/kg intravenous m-THPC (Biolitec AG, Jena, Germany). During
the 48 hours between administration and therapeutic illumination,
patients were sent home with a lux meter (Voltcraft, Oldenzaal, the
Netherlands) and with instructions to remain under subdued light
conditions.

[0038] At the time of treatment a special designed applicator of present
invention was placed in the anal cavity. During treatment this applicator
contains the treatment fiber, 5 cm linear diffuser (CeramOptec, Jena,
Germany), and four fiber optic probes, 1 cm linear diffusers (CeramOptec,
Jena, Germany) and FDPS probes, to monitor fluence (rate), fluorescence,
saturation and blood volume during therapeutic illumination. The
applicator was placed with the treatment fiber and the two linear
diffusers to measure fluence (rate). After placement of the applicator,
FDPS probes were placed to prevent damage or perforation of the anal
mucosa upon insertion due to the steel casing of these probes. Finally an
occluding cloth was applied at the base of the applicator to prevent
illumination of normal skin around the perianal region. Before
illumination, saturation and blood volume were measured to acquire
pre-illumination values. Based on the size of the lesion, a linear
diffuser of appropriate length was chosen to insert in the treatment
channel of the applicator. The fluence rate was measured in vivo at the
anal wall and set to 45-50 mWcm-2 which took on average 10 seconds.
Illumination was stopped when the desired dose, measured in vivo at the
anal wall, had been delivered. The delivered dose was between 10 and 17
Jcm-2. Fluence (rate) was measured at two opposite locations.
Treatment was stopped as soon as one of the probes indicated that the
desired fluence was reached, to prevent possible overtreatment of tissue
which could possibly lead to negative side effects, such as perforations
or anal dysfunction. After illumination the applicator was removed and as
a precaution the patient stayed in overnight to monitor response. The
acute response and the side effects associated by PDT were assessed in
the days following therapy.

Example 2

[0039] The radiation distribution of the applicator was investigated by
measuring along the applicator when immersed in scattering phantom
(intralipid diluted in water), with all measurement and treatment optical
fibers inserted. FIG. 4 shows the normalized measured fluence rate as
function of distance along the applicator, with the linear diffuser
located in the center channel of the applicator. Fluence rate was
measured in a longitudinal direction along the applicator at two sides,
one side where no measurement probes were located (open triangles) and
one side where measurement probes were located (open squares). The thick
black line represents the profile of the linear diffuser itself. The two
fluence rate profiles measured at the surface of the applicator at two
different sides both overlap with the fluence rate profile of the linear
diffuser on itself (i.e. profile of the linear diffuser measured outside
the applicator in the same phantom). Thus, it could be shown that the
applicator has little influence on the fluence rate profile of the linear
diffuser used for delivering the therapeutic radiation.

[0040] Additionally, radiation dosimetry was also assessed. FIG. 5 shows
the measured fluence rate as a function of delivered radiation dose for
two opposite locations (black and gray lines) in a single patient. In
different patients, and different locations, the fluence rate was found
to be constant, or gradually increasing or decreasing during therapeutic
irradiation. However the amounts of increase or decrease in fluence rate
were within 10%. At one location in a single patient a decrease in
fluence rate of 17% was observed.

Example 3

[0041] One of the advantages of FDPS is that it allows monitoring oxygen
saturation in blood (ratio between oxy- and deoxy-hemoglobin), blood
volume and fluorescence over the same volume. FIG. 6 shows the measured
saturation (open diamonds) and blood volume (open triangles) at a single
location during the course of treatment, i.e. before, during, and after
therapeutic illumination. The vertical lines indicate start and end of
therapeutic irradiation. This corresponds to a particular patient who
received a radiation dose of 17 J.cm-2. The saturation shows to be
relatively constant during illumination for this patient while the blood
volume shows oscillating behavior. FIG. 7 shows the fit and components of
a measured differential fluorescence spectrum and its residual. The
shallow peak at 720 nm is due to the presence of m-THPC.

[0042] Long wavelength fluorescence can also be measured. FIG. 8 shows a
fluorescence spectrum and its fit with the individual components and the
residual, acquired with the 1 cm linear diffusers on the opposite sides
of the applicator. In contrast to the differential fluorescence, the long
wavelength fluorescence measured by the linear diffusers interrogates an
unknown but larger volume than the FDPS signal. Since a different optical
filter was used in this setup it was not necessary to have a component
for the laser radiation.

[0043] Having described preferred embodiments of the invention with
reference to the accompanying drawings, it is to be understood that the
invention is not limited to the precise embodiments, and that various
changes and modifications may be effected therein by skilled in the art
without departing from the scope or spirit of the invention as defined in
the appended claims.